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When machines and brains mix, who's in charge? This is the type of problem pondered by neuroethicists such as UAB's Josh May, Ph.D., who examine questions at the crossroads of neuroscience and ethics.

Think about this: A 59-year-old Dutch man with advanced Parkinson’s disease is experiencing debilitating tremors. His doctors implant electrodes deep in his brain, which counteract the faulty signals but cause new troubles. The man starts behaving erratically, making grandiose claims, racking up sizable debts and generally making poor decisions. His doctors adjust the stimulation settings, and even prescribe mood stabilizing drugs, but they don’t help. Eventually, he has to make a choice: Stop the stimulation and be admitted to a nursing home, or keep it and be confined to a psychiatric ward.

This real-life dilemma, pulled from the pages of a Dutch medical journal, illustrates the ethical quandaries that arise from new mind-altering technologies such as deep-brain stimulation, says Josh May, Ph.D., an assistant professor in the UAB College of Arts and Sciences Department of Philosophy.

“The patient chose mental disorder over physical impairment,” said May. “But does a manic state limit one’s decisional capacity? Must we make sure his decision is made when he is suffering from the symptoms of Parkinson’s, free from an overactive mind prone to reckless behavior and delusions of grandiosity?”

These are the kinds of questions you’ll find at the crossroads of neuroscience and ethics, in a new field known as neuroethics. “Neuroscience attempts to understand and manipulate the brain, which is still largely a mystery,” May said. “That makes the ethics of its research especially tricky and fascinating. And it makes the results directly relevant to ethics itself, especially perennial questions about what drives moral and immoral action, how we think about morality, and whether we’re really in control of our actions.”

Brain scans are being used to advance longstanding arguments about ethical theories, for example. And researchers — May included — are taking advantage of the reach of the Internet to investigate ethical dilemmas in entirely new ways.

What follows is an edited version of an email conversation with Dr. May.

How are technologies like functional MRI being used to shape ethical debates?

Josh MayOne famous example involves a philosopher-turned-neuroscientist at Harvard University, Josh Greene. He argues that neuroimaging can help prove utilitarianism — the ethical theory that we should always and only maximize happiness for the greatest number of people. This means that sometimes the ends justify the means, even if the means to the greater good are the most horrific acts you can imagine.

Greene wants us to trust the utilitarian intuitions we have, which he argues arise from areas of the brain developed later in evolution, that are more characteristic of our ability to think carefully and override emotional responses. For example, people tend to think it’s immoral to push a large man off of a bridge so that his body stops a train from hitting five other innocent people (assuming only his body could stop the train). Greene says, don’t trust that response! Act for the greater good and push that man! Trust the part of your brain that can override that automatic response and do the cold calculation.

What do you think about this argument?

This research is fascinating and certainly adding to our knowledge of how our moral brains work. But I do have several worries about the ethical conclusions Greene draws. For example, the brain’s automatic, emotional responses are not clearly untrustworthy, as evidence suggests they’re quite flexible and subconsciously shaped by rational thought. While Greene argues such responses aren’t equipped to resolve complex contemporary moral problems, they may provide a shared moral framework that is precisely suited to resolving moral disputes. After all, if these intuitions are so engrained in the brain, then they may provide a kind of common moral currency.

In general, I think research on moral judgment is revealing that principles are more important to moral thinking than emotions, even for automatic responses. We certainly have biases, and emotions have their role, but morality involves complex social information and norms that we seem to tacitly navigate. Our automatic moral intuitions shouldn’t so easily be tossed aside, even if they conflict with utilitarianism, as they are guided by sophisticated information processing that is suited to rational social interaction.

So how do you do your research, given that it crosses disciplinary boundaries?

Philosophical research involves a lot of thinking for sure, as you have to consider arguments, objections, etc. Most of my research time is probably devoted to reading — hours upon hours of painstaking reading. Especially since my work straddles multiple disciplines, there’s always plenty to keep up on. Each article or chapter can take hours to read carefully, and I bet I read about 50 to 100 per year. While the reading is usually interesting, the writing is very poor and far from leisurely. The same goes for writing and revising my own papers. For me at least, a lot of my research ultimately involves thinking; but it’s often done while reading, writing or talking with other academics, although some of it does happen when I’m driving, cooking, watching a show, etc. I personally find it difficult to sit in silence for very long just thinking with my chin on my fist!

I do sometimes conduct my own experiments, which requires design, ethics approval, etc. But a large part requires assessing the results, reading about other research, formulating arguments, assessing objections and writing it all up — a whole lot of thinking beyond just data gathering!

And you’ve been doing some interesting experiments using Amazon’s Mechanical Turk service?

I’ve been using MTurk for several years now. It allows me to quickly gather responses from a diverse group of people online, instead of doing paper-and-pencil surveys around campus. Often the studies I do involve variations on the famous trolley problem, which pits promoting the greater good against violating people’s bodily rights.

For example, I’ll present participants with a version of a hypothetical scenario and ask them to provide their moral opinion about it — Did the person act wrongly? Then I compare the responses across scenarios that vary slightly in different respects, e.g., in whether the harm was brought about actively or passively, as a means to a goal or as an unintended side effect. Statistical analysis can tell us whether the differences are significant — providing evidence about whether the variable had a causal impact on responses. This technique — standard in so-called “experimental philosophy” — can help reveal the underlying distinctions and principles we make in moral judgment. I’ve followed a growing trend suggesting that our automatic intuitions are often in conflict with the prescriptions of utilitarianism, but I suggest that these intuitions aren’t necessarily due to factors that are morally irrelevant and so shouldn’t necessarily be rejected.

How might these issues affect everyday moral problems?

Here’s a medical example. Many people think a doctor shouldn’t help end a terminal patient’s life as a way to halt their immense suffering. That’s illegal in most states. But we don’t have such a problem with a doctor’s administering heavy doses of morphine to treat severe pain, even if she and the patient know it will hasten death. The patient’s death is then merely a foreseen and unintended side effect. Is this a quirk about euthanasia, or do we systematically treat harming as a mere side effect as more acceptable than harming as means?

I’m currently working on a series of studies that involve presenting participants with hypothetical cases in different contexts to see if their judgments change just based on the difference in how the harm was brought about. I hope this will inform whether the distinction is a viable one.

I understand you’ve been introducing UAB students to neuroethics with a course first offered this past spring?

It was a seminar, offered at the 200 and 400 levels, serving as a capstone for the Philosophy major. It was a blast! I had some excellent students, some of whom had backgrounds in neuroscience. Mike Sloane, the director of the University Honors Program, sat in as well, and he added some great insights from his discipline (psychology).

We covered a wide range of questions, including: Can the results of a brain scan constitute self-incrimination (thus violating the Fifth Amendment)? Does subconscious neural activity determine our behavior prior to conscious awareness? Is someone responsible for a criminal act if it was the result of a brain tumor? Do psychopaths have such an impaired understanding of morality that they can’t be liable for criminal acts? Which areas of the brain are responsible for moral thought and action? Is there something wrong with making oneself a better person by altering one’s brain directly (e.g., via pills or deep brain stimulation)? Can altering one’s brain yield a fundamentally different person? How does this affect consenting to brain interventions?

I’m hoping to cover similar topics in a future seminar, but perhaps down the line this could become a more regular offering.

The Rita Allen Foundation Scholars program supports basic biomedical research in the fields of cancer, immunology and neuroscience. Scholars are early-stage investigators and leaders in their respective fields who are advancing our understanding of the human condition.

Sorge’s research is primarily in the field of neuroscience, specifically focused on pain. His lab explores the interplay between addiction and pain, as well as the role of the immune system in pain sensitivity. As a scholar in pain research, Sorge will be granted $50,000 per year for up to three years to support his work.

The Rita Allen Foundation Scholars program has supported more than 140 scientists since 1976. The program embraces innovative research with above-average risk and groundbreaking possibilities. Scholars have gone on to win the Nobel Prize in Physiology or Medicine, the National Medal of Science, the Wolf Prize in Medicine, and the Breakthrough Prize in Life Sciences.

“By investing in outstanding biomedical scientists at the early stages of their careers, we are providing resources to these scholars to pioneer new approaches and discoveries,” said Elizabeth Christopherson, president and chief executive officer of the Rita Allen Foundation. “Researching basic biological questions is essential to improving human health and alleviating suffering caused by cancer, chronic pain, mental illness and other maladies.”

Sorge joins a prestigious class of scholars, with other recipients representing Columbia University, the University of Pennsylvania, New York University and others.

Smita Bhatia, M.D., M.P.H., director of UAB's new Institute for Cancer Outcomes and Survivorship, explains how cancer treatments can lead to chronic health conditions in later life — and how "survivorship clinics" will help.

Written by Matt Windsor

This article is adapted from a video interview with Dr. Bhatia on UAB’s MD Learning Channel.

Even after cancer is defeated, it can cast a lifelong shadow. “Cancer survivorship represents a very critical phase,” said Smita Bhatia, M.D., M.P.H., a pediatric oncologist and director of the new Institute for Cancer Outcomes and Survivorship in the UAB School of Medicine and associate director for cancer outcomes research at theUAB Comprehensive Cancer Center. “We and others have shown in our research studies that our cancer survivors are a vulnerable population,” she said. “When you follow them long-term, you find that they have a very high burden of chronic health conditions.”

Often, these health problems can be linked back to cancer treatments, including chemotherapy, radiation and even surgeries, Bhatia said. Because these complications can occur “many years after the completion of treatment,” they are called “late effects.” One example involves a particular class of chemotherapy drug known as anthracyclines. “We use these agents often because they are highly effective in a large variety of cancers,” Bhatia said. But research shows that patients who take these drugs have a high risk of developing congestive heart failure many years later.

Girls who have “received radiation to the chest around puberty for lymphoma,” have “an increased risk of breast cancer,” Bhatia added. And this breast cancer “occurs at a much younger age than would be anticipated in the general population. So these girls are developing breast cancer at age 30 and 40, whereas in the general population you’d be anticipating breast cancer at age 60.”

Results from a survey have shown that only a third of patients realize they are at risk for these late effects, and because the family practitioners and internists who are seeing these patients do not encounter cancer survivors very often, “it is not in the forefront in terms of their understanding, in terms of their knowledge base and in terms of their experience of what they should anticipate,” Bhatia said. Addressing this situation becomes even more urgent as the number of survivors grows, she adds. “The number of cancer survivors is growing at the rate of about 2 percent every year,” Bhatia said. “We will, by about 2022, have 18 million cancer survivors.”

“In order to provide the most comprehensive long-term care to our survivors, we need care plans. These “are essentially a summary of all the treatment that the patients received for their particular cancer, along with recommendations for long-term follow-up in order to detect complications.”

That is why UAB is establishing special survivorship clinics. “In order to provide the most comprehensive long-term care to our survivors, we need care plans,” Bhatia said. These “are essentially a summary of all the treatment that the patients received for their particular cancer, along with recommendations for long-term follow-up in order to detect complications.”

The idea, Bhatia said, is to lay out “a roadmap for our cancer survivors for life. That’s what I would like to do for all our cancer survivors who are coming to UAB, no matter what diagnosis they have, no matter what their age is, from here on.”

Survivorship clinics are staffed by physicians, nurse practitioners, social workers, psychologists, and dietitians, “who provide absolutely comprehensive but very tailored care to the survivors,” Bhatia said. “So we would, for example, do heart tests in order to detect heart failure at an earlier stage only amongst patients who’ve received treatments that are toxic to the heart. Mammograms would be recommended for patients who’ve received radiation to the chest at a young age, and who are at risk for breast cancer.”

This “very tailored but anticipatory screening” is designed “to detect these complications at an earlier stage,” said Bhatia.

The same survivorship model can now be extended to care for patients with many different chronic health conditions, Bhatia says. These include patients with sickle cell disease, HIV, congenital heart disease — “any chronic condition where the health care providers can really coordinate the care of the patient as a whole, the entirety of their health, and provide complete and comprehensive care long-term.”

Naloxone kits have prevented more than 10,000 deaths from opioid overdose since local distribution programs began in 1996. Now, as deaths from opioid overdose reach an all-time high in the United States, a crowdfunded project from UAB researchers aims to put naloxone in the hands of those at highest risk.

Written by Lesley McCollum

Deaths from opioid overdose are at an all-time high across the United States, and Birmingham has been hit particularly hard. In the past four years, heroin overdose deaths in Jefferson County and surrounding areas rose from 12 individuals to 137. But a team of UAB researchers is taking action to respond.

The group is led by Karen Cropsey, Psy.D., an associate professor in theUAB School of MedicineDepartment of Psychiatry and Behavioral Neurobiology. Cropsey specializes in substance abuse treatment in vulnerable populations; some of her current research programs involve treatment of individuals in the criminal justice system and people living with HIV/AIDS. She regularly witnesses the devastation of prescription opioid and heroin overdose in Birmingham. “I felt like there was something we could do about that,” she said.

To combat the rising rates of death from overdose, Cropsey and her team are exploring the distribution of naloxone kits directly to individuals with opioid addictions, or their caregivers. Using naloxone isn't a new idea. It's been the standard of care for opioid overdose in emergency rooms, including at UAB, since the early 1970s. The kits offer a last resort option to reverse an opioid overdose and prevent death. Several states, including California, New Mexico and Massachusetts, have successful local distribution programs for naloxone. In 2010 the CDC reported that since the first local distribution programs began in 1996, naloxone kits have prevented more than 10,000 deaths from opioid overdose.

Naloxone to the people

Cropsey and her colleagues want to bring a naloxone program to Birmingham as well. But “our program is different,” Cropsey said. Instead of distributing naloxone kits to first responders and law enforcement officers — the typical model — the UAB team wants to try a new approach: prescribing kits to individuals.

By taking advantage of the new Crowdfunding at UAB site, Cropsey’s team raised grassroots financial support for a unique study. In 30 days, the team collected $11,500 in pledges — enough to purchase more than 200 naloxone kits. Now they’re working to get the kits into the hands of the people who need them most: active opioid and heroin users.

The researchers are now hanging flyers around Birmingham and screening individuals interested in participating. They will be collecting information on how many kits are used, how many deaths they prevented and if participants follow up with treatment options after using naloxone. “I want to demonstrate that these kits can save lives,” Cropsey said.

Participants in the study are receiving training “on how to recognize signs of opioid overdose and how to administer the naloxone,” Cropsey said. They are instructed to then call 911 and go to the emergency room. Training is also being offered to friends or family members. It’s analogous to an EpiPen for someone with allergies, or insulin for someone with diabetes, Cropsey says the person who is prescribed the treatment may not be able to use it when it’s needed.

How naloxone works

When a person overdoses on an opioid, their breathing starts to slow down. After about one to two hours — or as short as a few minutes — breathing slows to a stop. This leaves a narrow but vital window to intervene. Opioids such as heroin or prescription drugs, including hydrocodone and oxycodone, work by latching on to receptors in the brain that produce their powerful effects. Naloxone rapidly displaces these drugs and then occupies the receptors so the opioid cannot return. Within minutes, the opioid is completely removed and the person who overdosed begins to breathe again.

But that success comes at a price. With complete removal of the opioid’s effects on the brain, naloxone puts the user into immediate, severe withdrawal. Imagine a sudden onset of the worst flu-like symptoms you’ve ever had, Cropsey explained. It’s “the nuclear option for people who would otherwise die.”

“They need to be alive to get treatment”

Working with such a stigmatized group of people brings challenges, Cropsey says. She often hears that people addicted to drugs should just quit — that they choose to be addicted in the first place and need to choose to stop. But while addiction does start as a choice, Cropsey explains, it doesn’t take long for a user’s system to get hijacked by the drugs.

Besides, many of us are dealing with the consequences of choices that negatively affect our health, she adds. Whether it’s Type 2 diabetes or obesity from our eating habits, or lung cancer from smoking, a majority of the leading causes of death result from behavioral choices we make, Cropsey said. “Addiction is a medical disease just as much as heart disease or diabetes.”

In an ideal world, no one would use drugs, Cropsey said. “Unfortunately that’s not the case here. We don’t live in an ideal world.” More than 2.5 million people in the United States abuse prescription opioids or heroin. Addiction finds its way into the lives of our families, friends and coworkers, Cropsey said. “What would you do if this was your friend or family member?”

Cropsey acknowledges the argument that distributing kits is simply enabling addiction. Naloxone kits reduce harm of overdose by preventing death, she says, but they aren’t the complete picture. “The goal is to get people substance abuse treatment to help them stop using opioids,” Cropsey said. “But they need to be alive to get treatment.”

If you are actively using a prescription opioid or heroin, or are the friend or family member of an active user, and are interested in learning more about the program, call 205-975-4528 and ask about the naloxone study.

The challenge is to stifle the binding of inhibitory antibodies but retain activity of a blood enzyme.

Long ZhengA rare autoimmune disease creates sudden pain in the abdomen or the head, sending a patient to the emergency room with a potentially fatal condition. The pain comes from a multitude of blockages of tiny blood vessels, formed after the patient’s own immune system somehow inhibits an enzyme that is vital to control clotting.

The syndrome is called thrombotic thrombocytopenic purpura, or TTP, and treatment involves exchanging three to seven liters of plasma each day, at a cost of $10,000 a day. This costly care may continue for several weeks or months.

Long Zheng, M.D., Ph.D., the Robert B. Adams Endowed professor and director of the Division of Laboratory Medicine at the University of Alabama at BirminghamDepartment of Pathology, wants to create a faster and more effective treatment for these patients. This has led Zheng and colleagues to molecular-level studies of the antibody that inactivates a blood enzyme, called ADAMTS13. ADAMTS13 recognizes and cuts a blood adhesion protein called von Willebrand factor. The inhibition of ADAMTS13 activity by the antibody in TTP patients allows ultra-large von Willebrand factor to form disseminated microvascular clots.

The ability of ADAMTS13 to recognize von Willibrand factor is exquisitely sensitive, somewhat like a fan who goes to a football game with 50,000 people and yet recognizes his cousin out of all the faces in the crowd. Similarly, the ability of the autoimmune antibodies in a TTP patient to recognize and bind to the patient’s own ADAMTS13 enzyme is also exquisitely sensitive, picking only ADAMTS13 out of all the other possible “self” proteins in the body.

Learning the molecular details of these two recognition abilities will help Zheng subtly alter ADAMTS13, to produce a therapeutic enzyme that can elude recognition by the autoimmune antibodies, yet still retains its activity to cleave von Willebrand factor. Such an engineered enzyme could be given to TTP patients in the hospital to speed recovery and slash the cost of treatment.

In a paper published in the Proceedings of the National Academy of Sciences, “High Resolution Epitope Mapping by HX MS Reveals the Pathogenic Mechanism and a Possible Therapy for Autoimmune TTP Disease,” senior author Zheng and colleagues report on those molecular details. The results reveal, for the first time, the mechanism of the inhibition of ADAMTS13 by autoantibodies and suggest an avenue for therapeutic intervention.

“This was really surprising. It’s like a table with five legs. If you take one away, it should still stand, but somehow it collapsed. This suggests that you need the coordinated activity of all five.”

The researchers found that five small loops in the protein’s amino acid sequence are necessary for the autoantibodies to bind to ADAMTS13. Cutting or substituting several amino acids out of any single one of the five loops prevented binding; furthermore, those small deletions in any single one of the five small loops also left the enzyme unable to cut von Willebrand factor.

“This was really surprising,” Zheng said. “It’s like a table with five legs. If you take one away, it should still stand, but somehow it collapsed. This suggests that you need the coordinated activity of all five.”

Thus, it appears that the autoimmune antibodies in TTP patients inhibit the enzyme by physically blocking the recognition site of ADAMTS13 for von Willebrand factor. More importantly, analysis of autoantibodies from 23 more TTP patients found that most use the same binding site, suggesting that a modified ADAMTS13 enzyme by protein engineering may be able to help a wide range of TTP patients.

Details of the research

The five years of research for this paper included the labs of Don L. Siegel, M.D., Ph.D., an expert in phage display, and S. Walter Englander, Ph.D., father of hydrogen exchange/mass spectrometry analysis to measure the protein-protein interaction regions of large proteins. Both Siegel and Englander are at the Perelman School of Medicine at the University of Pennsylvania, where Zheng used to work before moving to Birmingham.

The researchers first isolated messenger RNAs that code single chains of variable region of the monoclonal antibodies from B cells of patients with acquired TTP. They used a technique called phage display to select the messenger RNAs that code specific antibodies that bind and inhibit ADAMTS13. These monoclonal antibodies are then expressed in E. coli cells, purified, and biochemically characterized.

Of these, three inhibitory monoclonal antibodies were selected for further study by hydrogen-deuterium exchange coupled with mass spectrometry. This technology uses amine hydrogen (in H2O) exchange with deuterium (D2O) on each amino acid residue except proline. After reaction was stopped, the protein was then cut into small pieces (or peptide fragments) and run through HPLC for separation and mass spectrometry for identification. Antibody binding sites were detected by their ability to block the hydrogen and deuterium exchange, as compared with ADAMTS13 that was unbound.

One of the three high-affinity probes selected by phage display was used for the competition experiments against polyclonal autoimmune antibodies from 23 TTP patients. The results demonstrate that this particular binding epitope is common among patients with acquired autoimmune TTP.

Besides Zheng, co-authors are Veronica Casina, Wenbing Hu, Jianhua Mao, Rui-Nan Lu, Hayley Hanby, Brandy Pickens, Zhongyuan Kan, Woon Lim, Leland Mayne, Eric Ostertag, Stephen Kacir, Don Siegel and S. Walter Englander, all of the University of Pennsylvania. Zheng was recruited to UAB from the University of Pennsylvania in February and is the inaugural holder of the Robert B. Adams Endowed Professorship in Pathology in the UAB School of Medicine.